selatogrel (ACT-246475) / Idorsia, Viatris - LARVOL DELTA

Idorsia reaches an agreement with significant bondholders to restructure its convertible bond debt and to secure funding for future operations (Idorsia Press Release) - "Agreement with Viatris to revise collaboration for selatogrel and cenerimod results in the removal of significant cash requirement for 2025...In a third step of the restructuring, a special purpose vehicle (SPV) will be created. Idorsia intends to transfer to this SPV its rights to selatogrel and cenerimod, and its rights to aprocitentan. A bond exchange offer will be launched by the SPV, where the CB2025 and CB2028 bondholders will be offered the opportunity to exchange their convertible bonds for newly created notes issued by the SPV (SPV Notes)....Any potential net payments for milestones and royalties from selatogrel and cenerimod, as well as any potential net proceeds from a deal for aprocitentan will be used to repay holders of the SPV Notes."

Commercial • Cardiovascular • Lupus

SOS-AMI: Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrials.gov) - P3 | N=14000 | Enrolling by invitation | Sponsor: Idorsia Pharmaceuticals Ltd. | Trial completion date: Sep 2026 ➔ Aug 2025 | Trial primary completion date: Sep 2026 ➔ Aug 2025

Trial completion date • Trial primary completion date • Cardiovascular • Myocardial Infarction

SOS-AMI: Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrials.gov) - P3 | N=14000 | Enrolling by invitation | Sponsor: Idorsia Pharmaceuticals Ltd. | Trial completion date: Aug 2025 ➔ Sep 2026 | Trial primary completion date: Aug 2025 ➔ Sep 2026

Trial completion date • Trial primary completion date • Cardiovascular • Myocardial Infarction

Viatris and Idorsia Enter Into Significant Global Research and Development Collaboration (PRNewswire) - "Viatris Inc...announced they have entered into agreements for a significant global research and development collaboration under which Viatris will receive exclusive global development and commercialization rights to two Phase 3 assets as well as the potential to add additional innovative assets in the future. The collaboration includes selatogrel, a potential life-saving self-administered medicine for patients with a history of acute myocardial infarction (AMI), or heart attack, and builds on Viatris' existing global cardiovascular franchise and specialty infrastructure, as well as its knowledge, leadership, and distribution capabilities for self-administered medication for acute life-threatening conditions. The collaboration also includes cenerimod, a novel immunology asset that has the potential to be a first-in-class oral therapy for the treatment of systemic lupus erythematosus (SLE), the most common form of lupus....The transaction is expected to close at the end of March."

Licensing / partnership • Acute Coronary Syndrome • Cardiovascular • Immunology • Lupus • Myocardial Infarction • Systemic Lupus Erythematosus

Role of the P2Y12 receptor on thrombus formation and evolution in therapeutic strategies. (PubMed, Expert Opin Ther Targets) - No abstract available

Journal • Thrombosis

Enhancing the Speed of Antiplatelet Therapy in the High-Risk Patient: Inhaled Aspirin, Selatogrel, and RUC-4 (CRT 2024) - No abstract available

Clinical

SOS-AMI: Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrials.gov) - P3 | N=14000 | Enrolling by invitation | Sponsor: Idorsia Pharmaceuticals Ltd.

Trial completion date • Trial primary completion date • Cardiovascular • Myocardial Infarction

Clinical pharmacology of selatogrel for self-administration by patients with suspected acute myocardial infarction. (PubMed, Expert Opin Drug Metab Toxicol) - "In this review, the authors summarize the results from preclinical, phase 1, and phase 2 trials which showed that selatogrel provides rapid, pronounced, and reversible P2Y12 receptor inhibition with a favorable safety profile. These unique characteristics added to the limited potential to interact with co-medications and manageable PD interactions with other P2Y12 inhibitors provide a clear rationale for investigating the benefit of selatogrel as an emergency treatment to improve clinical outcomes in patients with AMI."

Journal • Review • Acute Coronary Syndrome • Cardiovascular • Coronary Artery Disease • Myocardial Infarction

Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists. (PubMed, Biomolecules) - " Scenarios with selatogrel 16 mg administration or placebo followed by a clopidogrel loading dose and, in turn, prasugrel or ticagrelor maintenance doses at different times of administration were studied. Model-based predictions informed the transition from selatogrel subcutaneous administration to oral P2Y therapy. The application of modeling techniques illustrates the value of employing pharmacokinetic and pharmacodynamic modeling for the simulation of various clinical scenarios of switching therapies."

Journal • Cardiovascular • Myocardial Infarction

In vitro comparison of platelet aggregation between zalunfiban and selatogrel in healthy donors (ESC 2023) - "Whole blood from healthy donors not taking aspirin (N=10) was anticoagulated with 3.2% TSC and 100 μM PPACK...Conclusion Selatogrel is a potent inhibitor of ADP-induced platelet aggregation, but has low impact on TRAP-induced platelet aggregation, whereas zalunfiban is a potent inhibitor of both ADP and TRAP-induced platelet aggregation. The difference between the drugs needs to be considered in light of the known generation of thrombin at the site of vascular injury within seconds."

Preclinical • Cardiovascular

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation. (PubMed, J Thromb Thrombolysis) - "An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors...Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events."

Journal • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction • Thrombosis

Dual Antiplatelet Therapy with Parenteral P2Y Inhibitors: Rationale, Evidence, and Future Directions. (PubMed, J Cardiovasc Dev Dis) - "Dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and an inhibitor of the platelet P2Y receptor for ADP, remains among the most investigated treatments in cardiovascular medicine...The latter have been shown to be extremely suitable in drug-naïve patients with acute coronary syndrome (ACS), mainly because oral P2Y inhibitors are associated with delayed efficacy in patients with STEMI and because pre-treatment with P2Y inhibitors is discouraged in NSTE-ACS, and in patients with recent DES implantation and in need of urgent cardiac and non-cardiac surgery. More definitive evidence is needed, however, about optimal switching strategies between parenteral and oral P2Y inhibitors and about newer potent subcutaneous agents that are being developed for the pre-hospital setting."

Journal • Review • Acute Coronary Syndrome • Cardiovascular • Hematological Disorders • Thrombosis

Inverse agonist efficacy of selatogrel blunts constitutive P2Y12 receptor signaling by inducing the inactive receptor conformation. (PubMed, Biochem Pharmacol) - "Specifically, using bioluminescence resonance energy transfer2 (BRET2) probes, selatogrel, ticagrelor, and elinogrel were shown to stabilize the inactive form of the Gi/o-G complex in cells with recombinant expression of the P2Y12 receptor. Selatogrel bound to pocket 1, spanning helix III to VII. Furthermore, the binding mode of selatogrel, suggesting steric overlap with the proposed binding site of ADP and the ADP analog 2-methylthioadenosine diphosphate (2MeSADP), agrees with the functional characterization of selatogrel preventing platelet activation by blocking ADP binding to the P2Y12 receptor."

Journal • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Thrombosis

Parenteral Antiplatelet Drugs in ST-Elevation Myocardial Infarction: Current Status and Future Directions. (PubMed, Thromb Haemost) - "Novel parenteral antiplatelet drugs, such as cangrelor, selatogrel, and zalunfiban, have been recently developed to achieve rapid, potent antiplatelet effects while preserving hemostasis. We provide a description of currently available parenteral antiplatelet agents and of those in clinical development for prehospital administration in STEMI patients."

Journal • Cardiovascular • Hematological Disorders • Myocardial Infarction • Thrombocytopenia

SOS-AMI: Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrials.gov) - P3 | N=14000 | Enrolling by invitation | Sponsor: Idorsia Pharmaceuticals Ltd. | Trial completion date: Feb 2024 ➔ Aug 2025 | Trial primary completion date: Feb 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Cardiovascular • Myocardial Infarction

Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of the P2Y12 receptor antagonist selatogrel. (PubMed, Clin Transl Sci) - "In conclusion, hepatic impairment alters the PK/PD relationship leading to prolonged effects. Therefore, dose adjustments may be warranted in subjects with moderate hepatic impairment."

Journal • PK/PD data • Cardiovascular • Hepatology • Myocardial Infarction

Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y Receptor Antagonist Selatogrel in Healthy Subjects. (PubMed, Clin Pharmacokinet) - P1 | "PK and simulated PD effects of selatogrel were similar across treatments."

Clinical • Journal • PK/PD data • Cardiovascular • Myocardial Infarction

The P2Y12 Receptor Antagonist Selatogrel Dissolves Preformed Platelet Thrombi In Vivo. (PubMed, J Clin Med) - "Dissolution was limited to the disintegration of the occluding part of the platelet thrombi, leaving small mural platelet aggregates to seal the blood vessel. Therefore, our experiments uncovered a novel advantage of selatogrel: the dissolution of pre-formed thrombi without the disintegration of haemostatic seals, suggesting a bipartite benefit of the early application of selatogrel in patients with acute thrombosis."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrialsregister.eu) - P3; N=14000; Ongoing; Sponsor: Idorsia Pharmaceuticals Ltd

Clinical • New P3 trial • Cardiovascular • Myocardial Infarction • CD9

Selatogrel and other P2Y12 inhibitors' putative off-target effects. (PubMed, J Cardiovasc Pharmacol) - No abstract available

Journal

SOS-AMI: Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrials.gov) - P3; N=14000; Enrolling by invitation; Sponsor: Idorsia Pharmaceuticals Ltd.; Not yet recruiting ➔ Enrolling by invitation

Enrollment open • Cardiovascular • Myocardial Infarction

SOS-AMI: Selatogrel Outcome Study in Suspected Acute Myocardial Infarction (clinicaltrials.gov) - P3; N=14000; Not yet recruiting; Sponsor: Idorsia Pharmaceuticals Ltd.

Clinical • New P3 trial • Cardiovascular • Myocardial Infarction

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y receptor between selatogrel and oral P2Y antagonists. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Long-term benefit is provided by oral P2Y receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. Determining the time point for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction."

Journal • PK/PD data • Cardiovascular • Myocardial Infarction

Selatogrel, a reversible P2Y12 receptor antagonist, has reduced off-target interference with haemostatic factors in a mouse thrombosis model. (PubMed, Thromb Res) - "In the presence of selatogrel the stability of hemostatic seals was unperturbed, translating to an improved blood loss profile. Our data suggest that the mechanism underlying the differences in blood loss profiles of P2Y12 receptor antagonists is by off-target interference with endothelial activation, neutrophil function and thus, fibrin-mediated stabilization of haemostatic seals."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

A Comparative Study of Selatogrel (ACT-246475) Formulations in Healthy Subjects (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Idorsia Pharmaceuticals Ltd.; Recruiting ➔ Completed

Clinical • Trial completion